title: USP1 deubiquitinase maintains phosphorylated CHK1 by limiting its DDB1-dependent degradation.
abstract: The maintenance of genetic stability depends on the fine-tuned initiation and termination of pathways involved in cell cycle checkpoints and DNA repair. Here, we describe a new pathway that regulates checkpoint kinase 1 (CHK1) activity, a key element controlling both checkpoints and DNA repair. We show that the ubiquitin-specific peptidase 1 (USP1) deubiquitinase participates in the maintenance of both total and phosphorylated levels of CHK1 in response to genotoxic stress. We establish that USP1 depletion stimulates the damage-specific DNA-binding protein 1-dependent degradation of phosphorylated CHK1 in both a monoubiquitinylated Fanconi anaemia, complementation group D2 (FANCD2)-dependent and -independent manner. Our data support the existence of a circuit in which CHK1 activates checkpoints, DNA repair and proliferating cell nuclear antigen and FANCD2 monoubiquitinylation. The latter two events, in turn, switch off activated CHK1 by negative feedback inhibition, which contributes to the downregulation of the DNA damage response. This pathway, which is compromised in the cancer-prone disease Fanconi anaemia (FA), likely contributes to the hypersensitivity of cells from FA patients to DNA damage and to the clinical phenotype of the syndrome; it may also represent a pharmacological target to improve patient care and develop new cancer therapies.
authors.affiliation: Genome Instability and Carcinogenesis UPR3081 CNRS, IGC, IMM, 31 chemin Joseph Aiguier, 13402 Marseille, France.
authors.forename: Jean-Hugues
authors.initials: JH
authors.lastname: Guervilly
authors.forename: Emilie
authors.initials: E
authors.lastname: Renaud
authors.forename: Minoru
authors.initials: M
authors.lastname: Takata
authors.forename: Filippo
authors.initials: F
authors.lastname: Rosselli
mesh_terms: D029681:Arabidopsis Proteins; D002453:Cell Cycle; D000071877:Checkpoint Kinase 1; D004249:DNA Damage; D004260:DNA Repair; D004268:DNA-Binding Proteins / Q000378:metabolism*; D015536:Down-Regulation; D010450:Endopeptidases / Q000235:genetics / Q000378:metabolism*; D005199:Fanconi Anemia / Q000235:genetics / Q000378:metabolism; D052236:Fanconi Anemia Complementation Group D2 Protein / Q000235:genetics / Q000378:metabolism; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D010641:Phenotype; D010766:Phosphorylation; D018809:Proliferating Cell Nuclear Antigen / Q000235:genetics / Q000378:metabolism; D011494:Protein Kinases / Q000378:metabolism*; D034741:RNA, Small Interfering; D015398:Signal Transduction; D014162:Transfection; D064570:Ubiquitin-Specific Proteases
chemical_list: D029681:Arabidopsis Proteins; C091435:DDB1 protein, human; D004268:DNA-Binding Proteins; D052236:Fanconi Anemia Complementation Group D2 Protein; D018809:Proliferating Cell Nuclear Antigen; D034741:RNA, Small Interfering; D011494:Protein Kinases; C000605867:CHEK1 protein, human; D000071877:Checkpoint Kinase 1; D010450:Endopeptidases; C579228:USP1 protein, human; D064570:Ubiquitin-Specific Proteases